title: Assessment of clofazimine activity in a second-line regimen for tuberculosis in mice.
abstract: BACKGROUND
  Although observational studies suggest that clofazimine-containing regimens are highly active against drug-resistant tuberculosis, the contribution of clofazimine for the treatment of this disease has never been systematically evaluated.
  
  
  OBJECTIVE
  Our goal was to directly compare the activity of a standard second-line drug regimen with or without the addition of clofazimine in a mouse model of multidrug-resistant tuberculosis. Our comparative outcomes included time to culture conversion in the mouse lungs and the percentage of relapses after treatment cessation.
  
  
  METHODS
  Mice were aerosol-infected with an isoniazid-resistant (as a surrogate of multidrug-resistant) strain of Mycobacterium tuberculosis. Treatment, which was administered for 5 to 9 months, was initiated 2 weeks after infection and comprised the following second-line regimen: daily (5 d/wk) moxifloxacin, ethambutol, and pyrazinamide, supplemented with amikacin during the first 2 months. One-half of the mice also received daily clofazimine. The decline in lung bacterial load was assessed monthly using charcoal-containing agar to reduce clofazimine carryover. Relapse was assessed 6 months after treatment cessation.
  
  
  RESULTS
  After 2 months, the bacillary load in lungs was reduced from 9.74 log10 at baseline to 3.61 and 4.68 in mice treated with or without clofazimine, respectively (P < 0.001). Mice treated with clofazimine were culture-negative after 5 months, whereas all mice treated without clofazimine remained heavily culture-positive for the entire 9 months of the study. The relapse rate was 7% among mice treated with clofazimine for 8 to 9 months.
  
  
  CONCLUSIONS
  The clofazimine contribution was substantial in these experimental conditions.
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. jgrosse4@jhmi.edu
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tyagi
authors.forename: Deepak V
authors.initials: DV
authors.lastname: Almeida
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Converse
authors.forename: Si-Yang
authors.initials: SY
authors.lastname: Li
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
authors.forename: Donald
authors.initials: D
authors.lastname: Enarson
authors.forename: Arnaud
authors.initials: A
authors.lastname: Trébucq
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002991:Clofazimine / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D008168:Lung / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012008:Recurrence; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D002991:Clofazimine